Anti-Notch3 agonist antibodies and their use in the treatment of Notch3-related diseases

Abstract

The present invention relates to agonist antibodies that specifically bind to Notch 3 and activate signaling. The present invention includes antibodies binding to an epitope comprising the first Lin12 domain. The present invention also includes uses of these antibodies to treat or prevent Notch 3 related diseases or disorders.

What is claimed is: 
     
       1. A method of activating Notch3 signaling in a cell comprising the step of contacting the cell with a monoclonal antibody that specifically binds to Notch 3 receptor, wherein the antibody specifically binds to an epitope in SEQ ID NO:10, and wherein the antibody activates Notch 3 receptor-mediated signaling through the Notch 3 receptor independent of ligand binding to the Notch 3 receptor. 
     
     
       2. The method of  claim 1 , wherein the antibody is an antigen-binding antibody fragment. 
     
     
       3. The method of  claim 1 , wherein the antibody is a single chain Fv. 
     
     
       4. The method of  claim 1 , wherein the antibody is a human, humanized, or chimeric antibody. 
     
     
       5. The method of  claim 1 , wherein the antibody comprises a variable heavy (VH) chain region comprising CDR-H1 of SEQ ID NO:4, CDR-H2 of SEQ ID NO:5, and CDR-H3 of SEQ ID NO:6, and a variable light (VL) chain region comprising CDR-L1 of SEQ ID NO:7, CDR-L2 of SEQ ID NO:8, and CDR-L3 of SEQ ID NO:9. 
     
     
       6. The method of  claim 5 , wherein the VH chain region comprises SEQ ID NO:2, and the VL chain region comprises SEQ ID NO:3. 
     
     
       7. The method of  claim 1 , wherein Notch 3 receptor-mediated signaling in the cell is increased by at least about 4-fold after activation with the antibody. 
     
     
       8. The method of  claim 1 , wherein Notch 3 receptor-mediated signaling in the cell is measured using a reporter assay. 
     
     
       9. The method of  claim 1 , wherein Notch 3 receptor-mediated signaling in the cell is measured by detecting Notch3 proteolytic cleavage. 
     
     
       10. The method of  claim 9 , wherein Notch3 proteolytic cleavage is detected using Immunohistochemistry or an enzyme-linked immunoabsorbent assay (ELISA). 
     
     
       11. A method of activating Notch3 signaling in a cell comprising the step of contacting the cell with a monoclonal antibody that specifically binds to Notch 3 receptor, wherein the antibody specifically binds to an epitope in SEQ ID NO:11, and wherein the antibody activates Notch 3 receptor-mediated signaling through the Notch 3 receptor independent of ligand binding to the Notch 3 receptor. 
     
     
       12. The method of  claim 11 , wherein the antibody is an antigen-binding antibody fragment. 
     
     
       13. The method of  claim 11 , wherein the antibody is a single chain Fv. 
     
     
       14. The method of  claim 11 , wherein the antibody is a human, humanized, or chimeric antibody. 
     
     
       15. The method of  claim 11 , wherein the antibody comprises a variable heavy (VH) chain region comprising CDR-H1 of SEQ ID NO:4, CDR-H2 of SEQ ID NO:5, and CDR-H3 of SEQ ID NO:6, and a variable light (VL) chain region comprising CDR-L1 of SEQ ID NO:7, CDR-L2 of SEQ ID NO:8, and CDR-L3 of SEQ ID NO:9. 
     
     
       16. The method of  claim 15 , wherein the VH chain region comprises SEQ ID NO:2, and the VL chain region comprises SEQ ID NO:3. 
     
     
       17. The method of  claim 11 , wherein Notch 3 receptor-mediated signaling in the cell is increased by at least about 4-fold after activation with the antibody. 
     
     
       18. The method of  claim 11 , wherein Notch 3 receptor-mediated signaling in the cell is measured using a reporter assay. 
     
     
       19. The method of  claim 11 , wherein Notch 3 receptor-mediated signaling in the cell is measured by detecting Notch3 proteolytic cleavage. 
     
     
       20. The method of  claim 19 , wherein Notch3 proteolytic cleavage is detected using Immunohistochemistry or an enzyme-linked immunoabsorbent assay (ELISA).